Despite increasing recognition that BPA has harmful effects on the reproductive, nervous and immune systems. While higher urine BPA concentrations are associated with cardiovascular disease in humans, the effect(s) of BPA at environmentally relevant concentrations on the heart is unknown. The aim of the proposed studies is to elucidate the in vivo sex-specific impacts that BPA has on cardiac physiology, to understand the underlying modes and mechanisms of action, and ultimately improve heart health through understanding the impact of pathological actions of exposure to BPA as a protypical environmental EDCs. The central hypothesis of the proposed studies is during development BPA negatively impacts cardiac function which may manifest later in life. It is therefore hypothesized that the harmful effects of BPA exposure will impact Ca++ handling, and that developmental exposures may alter the normal sex-specific actions of estrogen in the heart, and negatively impact heart health by increasing arrhythmias, altering hemodynamic function, and increasing cardiac dysfunction in response to physiologic conditions of stress (e.g. catecholamine and pressure overload induced hypertrophy/heart failure). As its primary endpoints, the proposed studies will focus on understanding the cardiac-specific actions of BPA. However, the proposal is far more crosscutting, and not limited to a single organ or system-based endpoint. Along with the cardiac specific end-points, a number of physiological and reproductive endpoints "classically" used to assess estrogenic EDC activity will be characterized. This will allow direct comparison of results obtained in the "estrogen-sensitive" C57BL/6J strain with studies performed in the "insensitive" CD1 (Swiss) mouse. Detailed physiological phenotype data will be collected for all animals and at termination of the study complete necropsy will be performed with tissues from all organs harvested, collected and prepared for histological studies with paired samples preserved for future molecular, epigenetic, and "omics" analysis. As a result of the proposed studies a defining framework and knowledge base necessary to standardize future studies that employee C57BL/6J derived genetic mouse models will be created, and allow systematic investigation of the mechanisms of action of BPA using knockout and transgenic models. PUBLIC HEALTH RELEVANCE: Endocrine disrupting chemicals acting on the estrogen system: estrogenic endocrine-disrupting chemicals (EDCs) are a structurally diverse group of compounds that mimic or antagonize the effects of endogenous estrogens. Bisphenol A (BPA) is an EDC used extensively in the production of consumer products such as polycarbonate plastics, food cans and plastic packaging, dental sealants and water pipes. Analysis of BPA in urine samples showed that BPA is present essentially all of the US population at levels demonstrated to harm negative effects on the reproductive function and have harmful impacts on cancer. Despite increasing recognition that BPA has harmful effects on the reproductive, nervous and immune systems, the effect(s) of BPA at environmentally relevant concentrations on the heart is unknown. Higher urine BPA concentrations are associated with cardiovascular disease in humans. In contrast to the perception that "female hormones" protect women from CV disease, disease of the cardiovascular system is the leading cause of mortality for women in the US. Since 1984, more women than men have died of CV disease every year in the US;fifty-three percent of total CV disease deaths occur in women. Women, especially prior to menopause, have lower rates of coronary heart disease and myocardial infarction (MI). However, women have a much worse prognosis following MI. The overall post-MI mortality rate is higher for women. For peri-menopausal women (<55 years) the post-MI mortality rate is more than double that of same aged men. A significant contributing factor to the worse prognosis following MI for women is arrhythmia. Women have more ventricular fibrillation-complications following MI, and a much higher arrhythmic death rate than men during the first 6 months post-MI Women also have unique sensitivities to arrhythmias. For example, women are at increased risk of arrhythmia during pregnancy coincident with increasing levels of estrogens. To address the role of estrogens in conferring unique benefits or risks associated with CV disease of women, it is critical to understand the differences between the male and female CV system and how endogenous "female hormones" influence cardiac function. Understanding the unique protective or harmful actions of endogenous and environmental estrogens will result in new strategies to decrease the incidence of CV disease and increase survival of both men and women with CV disease. The proposed studies the proposed studies focus on understanding the cardiac-specific actions of BPA and are of very broad and extremely high impact. In fact, the results of these studies could impact understanding related to cardiovascular health of nearly 100% of the US population.